CN102898388A - Method for synthesizing substituted benzo[alpha]phenazine compound - Google Patents
Method for synthesizing substituted benzo[alpha]phenazine compound Download PDFInfo
- Publication number
- CN102898388A CN102898388A CN2012103635712A CN201210363571A CN102898388A CN 102898388 A CN102898388 A CN 102898388A CN 2012103635712 A CN2012103635712 A CN 2012103635712A CN 201210363571 A CN201210363571 A CN 201210363571A CN 102898388 A CN102898388 A CN 102898388A
- Authority
- CN
- China
- Prior art keywords
- formula
- reaction
- halogenated aryl
- methyl
- quinoxaline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Abstract
The invention provides a method for synthesizing a substituted benzo[alpha]phenazine compound, which comprises the following steps: synthesizing 2-(2-haloaryl)-3-methyl quinoxaline (I) from 2-haloaryl ethyl ketone and substituted o-phenylenediamine used as raw materials; generating 2-(2-haloaryl)-3-vinyl quinoxaline (II) through the reaction with N-methyl amide in the presence of an iron catalyst; and finally, obtaining the substituted benzo[alpha]phenazine compound (III) through Heck cyclization reaction.
Description
Technical field
The present invention relates to the novel method of a kind of synthesizing substituted also [α] azophenlyene compounds.
Background technology
Benzo [α] azophenlyene compounds is the important organic compound that a class has biologic activity.In recent years, owing to its outstanding biological activity that shows at anti-malarial, anti-hepatitis and the aspect such as antitumor is subject to extensive concern
[1]At present, the traditional technology of synthesizing substituted also [α] azophenlyene compounds mainly contains following several: a): take naphthols as raw material, obtain replacing benzo [α] azophenlyene compounds through steps such as peroxidation chemical combination, its advantage is that step is short, but shortcoming is also very obvious, expansion such as substrate is relatively poor, and yield is not high, is not the synthetic route of a simple general-purpose
[2]B): take naphthylamines as raw material through with the coupled reaction of 2-halo-3-nitro-aromatic compound, obtain product through steps such as reductive ring closures again, exist equally the problems such as substrate is difficult to obtain, universality is low, yield is not high
[3]Therefore, one by being simple and easy to such an extent that the raw material synthetic corresponding universal method that replaces benzo [α] azophenlyene compounds of setting out is anxious to be developed to solve the above problems.
Summary of the invention
In recent years, the organic catalyzed reaction with its efficient katalysis and novelty of metal more and more is applied among the structure of some complicated aromatic rings.The present invention is exactly under this background, take the coupling carbon-to-carbon coupling synthesizing ethylene based compound of the metal catalytic of independent development as committed step, again forefathers' work has been changed with application and development one directly to contain various substituent 2-halogenated aryl ethyl ketones as raw material, after α-bromination, generate the 2-(2-halogenated aryl with the substituted o-phenylenediamine cyclization)-the 3-methyl-quinoxaline, leave the vinylation reaction that " the N-methyl " captured in the N-methyl nitrosourea realizes methyl at iron catalyst and oxygenant, generate the 2-(2-halogenated aryl)-3-vinyl quinoxaline, generate replacement benzo [α] azophenlyene by the Heck ring closure reaction at last.
Concrete, the technical solution used in the present invention is:
A kind of method of synthetic replacement benzo [α] azophenlyene compounds shown in formula III, described method is: take the 2-halogenated aryl ethyl ketone shown in the formula IV as raw material, after α-bromination, carry out ring-closure reaction with the substituted o-phenylenediamine shown in the formula V, 2-(2-halogenated aryl shown in the synthesis type I)-the 3-methyl-quinoxaline, 2-(2-halogenated aryl shown in the formula I)-the 3-methyl-quinoxaline in the presence of iron catalyst and oxygenant with the reaction of N-methyl nitrosourea shown in the formula VI, 2-(2-halogenated aryl shown in the production II)-3-vinyl quinoxaline, 2-(2-halogenated aryl shown in the formula II)-3-vinyl quinoxaline carries out the Heck ring closure reaction under the palladium catalyst effect, generate replacement benzo [α] the azophenlyene compounds shown in the formula III;
Among formula I, formula II, formula III or the formula IV, R
1, R
2, R
3, R
4Independent separately is H, methyl, methoxyl group, phenyl, F, Cl, Br, I, NO
2, CF
3, COO CH
3, COO C
2H
5, CN; Or R
2, R
3Connect into ring with its two carbon that connect on the phenyl ring, form a new phenyl ring; Preferably, described R
1, R
2, R
3, R
4All be H; Or R
1, R
3, R
4Be H, R
2Be methoxyl group; Or R
1, R
4Be H, R
2, R
3Connect into ring with its two carbon that connect on the phenyl ring, form a new phenyl ring;
Among formula I, formula II, formula III or the formula V, R
5, R
6, R
7, R
8Independent separately is H, methyl, Cl, phenyl, COO CH
3Preferred R
5, R
6, R
7, R
8All be H
Among formula I, formula II or the formula IV, X is Cl, Br or I, is preferably Br;
Among the formula VI, R is H, methyl or phenyl, is preferably methyl.
Further, said method comprising the steps of:
(1) the 2-halogenated aryl ethyl ketone shown in the formula IV is dissolved the rear bromine simple substance that splashes into ether or methylene dichloride under room temperature, dropwised under room temperature stirring reaction 15 ~ 60 minutes, then in reaction mixture, add the saturated sodium thiosulfate solution washing to colourless, separatory is got the organic phase drying, the decompression desolvation, the gained crude product is alpha-brominated 2-halogenated aryl ethyl ketone, and crude product is dissolved with acetonitrile, adds HClO
4SiO
2Substituted o-phenylenediamine shown in catalyzer and the formula V, at room temperature (preferred 60 ℃) stirring reaction under reflux temperature, TLC follows the tracks of and detects to the reaction end, gained reaction solution a aftertreatment obtains the 2-(2-halogenated aryl shown in the formula I)-the 3-methyl-quinoxaline; 2-halogenated aryl ethyl ketone shown in the described formula IV is 1:1.0 ~ 1.5 with the ratio of the amount of substance of bromine simple substance, preferred 1:1.2; Described alpha-brominated 2-halogenated aryl ethyl ketone is 1:1 ~ 5 with the ratio of the amount of substance of the substituted o-phenylenediamine shown in the formula V, preferred 1:2; The amount of substance of described alpha-brominated 2-halogenated aryl ethyl ketone comes in the amount of substance of the 2-halogenated aryl ethyl ketone shown in the formula IV;
(2) the 2-(2-halogenated aryl shown in the formula I)-the 3-methyl-quinoxaline is in the presence of iron catalyst and oxygenant, with the N-methyl nitrosourea reaction shown in the formula VI, 20 ~ 160 ℃ of temperature of reaction, TLC follows the tracks of and detects to the reaction end, and reaction solution b aftertreatment obtains the 2-(2-halogenated aryl shown in the formula II)-3-vinyl quinoxaline; Described iron catalyst is molysite or ferrous salt, and described oxygenant is persulphate,, the 2-(2-halogenated aryl shown in the described formula I)-ratio of the amount of substance of 3-methyl-quinoxaline, iron catalyst, oxygenant is 1:0.001 ~ 0.3:1 ~ 5; 2-(2-halogenated aryl shown in the described formula I)-concentration of 3-methyl-quinoxaline in the N-methyl nitrosourea shown in the formula VI is 0.01 ~ 2mol/L;
(3) the 2-(2-halogenated aryl shown in the formula II)-3-vinyl quinoxaline and palladium catalyst, inorganic silver salt additives be in rare gas element such as argon gas, nitrogen environment, add tertiary amine compounds and polar non-proton organic solvent, under 50 ~ 160 ℃ of temperature, carry out the Heck ring closure reaction, TLC follows the tracks of and detects to the reaction end, and reaction solution c separating treatment obtains replacement benzo [α] the azophenlyene compounds shown in the formula III; Described palladium catalyst is tetrakis triphenylphosphine palladium or three (dibenzalacetone) two palladiums, is preferably tetrakis triphenylphosphine palladium; 2-(2-halogenated aryl shown in the described formula II)-ratio of the amount of substance of 3-vinyl quinoxaline, palladium catalyst, inorganic silver salt additives, tertiary amine compounds is 1:0.001 ~ 0.15:1 ~ 4:1 ~ 10.
In the described step (1), described HClO
4SiO
2The quality consumption of catalyzer is counted 20 ~ 150mg/mmol with the amount of substance of alpha-brominated 2-halogenated aryl ethyl ketone, preferred 70mg/mmol, the amount of substance of described alpha-brominated 2-halogenated aryl ethyl ketone comes in the amount of substance of the 2-halogenated aryl ethyl ketone shown in the formula IV.
In the described step (1), the volumetric usage of described ether or methylene dichloride is counted 1 ~ 5mL/mmol with the amount of substance of the 2-halogenated aryl ethyl ketone shown in the formula IV usually.
In the described step (1), described acetonitrile volumetric usage usually count 1 ~ 10mL/mmol with the amount of substance of the 2-halogenated aryl ethyl ketone shown in the formula IV.
HClO in the described step (1)
4SiO
2Be according to document A. K. Chakraborti, the method among the R. Gulhane. Chem. Commun. 2003,1896. prepares.
In the described step (1), described reaction solution a post-treating method is: after reaction finishes, reaction solution a filters, the filtrate decompression desolventizing, separate through the column chromatography chromatogram method, with take sherwood oil or hexanaphthene and ethyl acetate preferred 6 ~ 15 ︰ 1 of 2 ~ 30:1(by volume) solvent that mixes is as eluent, collect elutriant steam desolventize the 2-(2-halogenated aryl that obtains shown in the formula I)-the 3-methyl-quinoxaline.
In the described step (2), vinylated reagent is the N-methyl nitrosourea shown in the formula VI, in the presence of iron catalyst and oxygenant, capture the carbon atom in " N-methyl " structural unit in the N-methyl nitrosourea, thereby methyl is vinylated in the realization substrate, reach the purpose that increases carbochain, also successfully made up the carbon skeleton structure that replaces phenonaphthazine simultaneously.The N-methyl nitrosourea of selecting comprises N, dinethylformamide (DMF), N, N-N,N-DIMETHYLACETAMIDE (DMA) or N, N-dimethyl benzamide etc., when making vinylated reagent also as the reaction solvent, 2-(2-halogenated aryl shown in the substrate formula I)-and the concentration of 3-methyl-quinoxaline in the N-methyl nitrosourea shown in the dissolvant type VI is being proper between 0.01 ~ 2mol/L, best concentration is 0.1 mol/L.The complete solvent of unreacted can be recycled, and has certain industrial prospect.
In the described step (2), the 2-(2-halogenated aryl shown in the formula I)-ratio of the amount of substance of 3-methyl-quinoxaline, iron catalyst, oxygenant is 1:0.001 ~ 0.3:1 ~ 5, is preferably 1:0:01 ~ 0.1:1.5 ~ 3, most preferably is 1:0.025:2.
Described iron catalyst is molysite or ferrous salt, be preferably iron trichloride, ferric sulfate, iron nitrate, ferric acetyl acetonade, ferrous sulfate, iron protochloride, Iron(III) chloride hexahydrate, Iron dichloride tetrahydrate, Fe(NO3)39H2O or ferrous sulfate, Iron(III) chloride hexahydrate (ferric sesquichloride) more preferably, FERRIC CHLORIDE ANHYDROUS, ferrous sulfate, Iron dichloride tetrahydrate or Fe(NO3)39H2O.The benefit that contains the inorganic molysite of crystal water is to deposit easy to use, cheaply is easy to get and active high.
Described oxygenant is persulphate, is preferably ammonium persulphate, Potassium Persulphate, Sodium Persulfate or potassium hydrogen persulfate composite salts, more preferably ammonium persulphate or Potassium Persulphate, most preferably Potassium Persulphate.
The vinylation reaction of described step (2) all can be carried out in a wider range of reaction temperature, and the recommendation response temperature is 20 ℃ ~ 160 ℃, and preferred 60 ~ 120 ℃, most preferably temperature of reaction is 110 ℃.Following the tracks of detection to reaction with TLC in the reaction process finishes.The time range of reaction is wider, between 0.5 hour to 12 hours, under preferred catalyzer, oxygenant, concentration of substrate and temperature, usually can finish reaction at 2 hours to 6 hours, needs in some instances by prolonging the reaction times to improve yield.
In the described step (2), described reaction solution b post-treating method is: after reaction finishes, reaction solution b filters, filtrate adds the ether dilution, after the saturated common salt water washing, to get to steam after the organic phase drying and desolventize, residuum is through column chromatography for separation, take sherwood oil or hexanaphthene and ethyl acetate preferred 8 ~ 15 ︰ 1 of 2 ~ 30:1(by volume) solvent that mixes is as eluent, collect elutriant steam desolventize the 2-(2-halogenated aryl that obtains shown in the formula II)-3-vinyl quinoxaline.
In the described step (3), 2-(2-halogenated aryl shown in the described formula II)-ratio of the amount of substance of 3-vinyl quinoxaline, palladium catalyst, inorganic silver salt additives, tertiary amine compounds is 1:0.001 ~ 0.15:1 ~ 4:1 ~ 10, preferred 1:0.02 ~ 0.1:1 ~ 2: 2 ~ 4, most preferably 1:0.05:2: 4.
In the described step (3), described tertiary amine compounds is triethylamine, Tri-n-Propylamine or DIPEA, preferred triethylamine.
In the described step (3), described inorganic silver salt additives is Sulfuric acid disilver salt or Silver Nitrate, preferably sulfuric acid silver.
In the described step (3), described polar non-proton organic solvent is N,N-dimethylacetamide or DMF, preferred N,N-dimethylacetamide.The consumption of described polar non-proton organic solvent is with the 2-(2-halogenated aryl shown in the formula II)-amount of substance of 3-vinyl quinoxaline counts 10 ~ 50mL/mmol.
The temperature of reaction of described step (3) is 50 ~ 160 ℃, is preferably 100-140 ℃, most preferably 140 ℃.
In the described step (3), described reaction solution c method for separating and processing is: after reaction finishes, reaction solution c filters, filtrate adds the ether dilution, after the saturated common salt water washing, to get to steam after the organic phase drying and desolventize, residuum is through column chromatography for separation, take sherwood oil and ethyl acetate preferred 8 ~ 15 ︰ 1 of 2 ~ 30:1(by volume) solvent that mixes is as eluent, and collect elutriant and steam and desolventize replacement benzo [α] the azophenlyene compounds that obtains shown in the formula III.
2-halogenated aryl ethyl ketone shown in the formula IV of the present invention can by common substituted aryl ethyl ketone through isonitrosomethyl, ortho position C-H activation halogenation, take off oxime and be reduced to ketone and make, D. Kalyani, A. R. Dick, W. Q. Anani, M. S. Sanford. Tetrahedron 2006, aforesaid method is disclosed in 62,11483.Reaction formula is as follows:
Concrete, described method is, will be suc as formula aryl ethyl ketone and the CH shown in the VII
3ONH
2HCl, pyridine reflux in methanol solvate, stirring reaction 12 ~ 30 hours, reaction finishes to be cooled to room temperature, reaction solution removes under reduced pressure in the backward resistates of solvent and adds water, use extracted with diethyl ether, get organic phase dry steam to desolventize by column chromatography for separation obtain the compound shown in the formula VIII, the compound shown in the formula VIII and N-bromosuccinimide (abbreviation NBS) are at Pd(OAc)
2Under the catalyst action, in acetic acid, be heated to 100 ~ 120 ℃ of stirring reactions 12 ~ 20 hours, the gained residuum was through column chromatography for separation after reaction end afterreaction liquid removed solvent under reduced pressure, obtain the compound shown in the formula IX, in the Isosorbide-5-Nitrae-dioxane solution of the hydrogenchloride of the 5mol/L that the compound adding shown in the formula IX is excessive, 80 ℃ of lower reacting by heating, TLC detects to the reaction end, and residuum obtained the 2-halogenated aryl ethyl ketone shown in the formula IV through column chromatography for separation after reaction solution removed solvent under reduced pressure; Aryl ethyl ketone and CH shown in the described formula VII
3ONH
2The ratio of the amount of substance of HCl, pyridine is 1:1.5 ~ 3:6 ~ 10; Compound shown in the described formula VIII and NBS, Pd(OAc)
2The ratio of amount of substance be 1:1 ~ 1.5:0.03 ~ 0.1.
Beneficial effect of the present invention is:
(1) reaction reagent comprises the low toxicities such as catalyzer, oxygenant and solvent and cheaply is easy to get.
(2) reaction conditions is gentle, and is simple to operate.
(3) substrate adaptability is good, and yield is high.
(4) raw material is easy to get, and reactions steps is simple, is a kind of general novel method of synthetic all kinds of replacement benzos [α] azophenlyene.
Replacement benzo [α] the azophenlyene substrate wide adaptability that the present invention synthesizes, substituting group in the raw material comprises hydrogen, alkyl, alkoxyl group, ester group, hydroxyl, amido, nitro, trifluoromethyl, halogen or aromatic group etc., can also be polysubstituted substituted aryl, heterocyclic aryl etc.In sum, this reaction provides a general variation route from synthesizing substituted also [α] azophenlyene of simple raw material, has certain industrial prospect.
Embodiment
The present invention will be further described by embodiment in following the present invention, but protection scope of the present invention is not limited to this.
HClO in the embodiment of the invention
4SiO
2Prepare by the following method: with 70% HClO
4The aqueous solution (1.25g) joins to stir in the ether suspension that is mixed with silica gel (24 g, 200-300 order) and spends the night, and pressurization removes solution, and the 100 ℃ of lower insulations in vacuum drying oven of gained solid were obtained HClO in 72 hours
4SiO
2Pressed powder.
Embodiment 1
[1] with 2-bromo Propiophenone (5.0 mmol), be dissolved in the 5mL ether, drip bromine (6.0 mmol) under the room temperature, wait to dropwise and continue to stir 40 minutes, add the saturated sodium thiosulfate solution washing in the system after colourless, separatory is got the organic phase drying, and removal of solvent under reduced pressure obtains alpha-brominated 2-bromo Propiophenone crude product, need not to purify directly to carry out ring closure reaction.Alpha-brominated 2-bromo Propiophenone with the dissolving of 10mL acetonitrile, is added HClO
4SiO
2(350 mg) and O-Phenylene Diamine (10 mmol), mixture are at 60 ℃ of lower stirring reactions, and TLC detects to the reaction end.Mixture after filtration, separate with column chromatography chromatogram method (the leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 15 ︰ 1) behind the filtrate decompression desolvation obtain faint yellow solid 2-(2-bromophenyl)-3-methyl-quinoxaline 0.998g(yield 67%).
[2] with the 2-(2-bromophenyl)-3-methyl-quinoxaline 119.2 mg (0.4 mmol), Iron(III) chloride hexahydrate 2.7 mg (0.01 mmol), Potassium Persulphate 216 mg(0.8 mmol), N,N-dimethylacetamide (4 mL) adds in the 25 mL flasks.110 ℃ of reactions of mixture heating up TLC detection reaction end after 3 hours, wash with saturated aqueous common salt (10 mL ⅹ 3) after adding the dilution of 20 mL ether, organic phase with anhydrous sodium sulfate drying after decompression slough solvent, obtaining weak yellow liquid 2-(2-bromophenyl with column chromatography chromatogram method (the leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 15 ︰ 1) separation)-3-vinyl quinoxaline 107.8 mg(87% yields).
[3] with the 2-(2-bromophenyl)-3-vinyl quinoxaline 46.5 mg (0.15 mmol), tetrakis triphenylphosphine palladium 7.3 mg(0.0075 mmol), Sulfuric acid disilver salt 94 mg(0.3 mmol) add successively in the dry reaction pipe of 10 mL.Be filled with argon gas after reaction tubes vacuumized, repeatable operation three times, under argon atmosphere with needle cylinder injection triethylamine 61 mg(0.6 mmol) and degassed dry N,N-dimethylacetamide 2 mL.With mixture reacting by heating 2 hours in 140 ℃ of oil baths.After the TLC detection reaction finishes, reaction solution is rear with saturated aqueous common salt (10 mL ⅹ 3) washing with the dilution of 15 mL ether, organic phase with anhydrous sodium sulfate drying after decompression slough solvent, obtaining yellow solid benzo [α] azophenlyene 28.6 mg(83% yields with column chromatography chromatogram method (the leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 15 ︰ 1) separation).
Yellow solid; R
f=0.42 (petroleum ether-EtOAc=6:1); Mp=142-143 ℃;
1H NMR (500 MHz, CDCl
3): δ=9.41 (d, J=8.5 Hz, 1H), (8.38-8.36 m, 1H), 8.30-8.28 (m, 1H), 8.01 (d, J=9.5 Hz, 1H), 7.97 (d, J=9.5 Hz, 1H), 7.91-7.86 (m, 3H), (7.82-7.76 m, 2H) ppm;
13C NMR (125 MHz, CDCl
3): δ=143.4,142.7,142.6,142.0,133.3,133.2,131.1,130.0,129.8 (2C), 129.7,129.2,128.2,127.9,127.1,125.4 ppm; MS (EI, 70eV): m/z (%)=230 (100) [M+].
Embodiment 2
[1] with 2-bromo-4-p-methoxy-phenyl ethyl ketone (5.0 mmol), be dissolved in the 5mL methylene dichloride, drip bromine (6.0 mmol) under the room temperature, wait to dropwise and continued stirring reaction 20 minutes, add the saturated sodium thiosulfate solution washing in the system after colourless, separatory is got the dry removal of solvent under reduced pressure of organic phase and is obtained alpha-brominated 2-bromo-4-p-methoxy-phenyl ethyl ketone crude product, need not to purify and directly carries out ring closure reaction.Alpha-brominated 2-bromo-4-p-methoxy-phenyl ethyl ketone with the dissolving of 10mL acetonitrile, is added HClO4SiO2(350 mg) and O-Phenylene Diamine (10 mmol), mixture is at 60 ℃ of lower stirring reactions, and TLC detection to reaction finishes.Mixture after filtration, separate with column chromatography chromatogram method (the leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 15 ︰ 1) behind the filtrate decompression desolvation obtain faint yellow solid 2-(2-bromo-4-p-methoxy-phenyl)-3-methyl-quinoxaline 1.05g (yield 64 %).
[2] with 2-(2-bromo-4-p-methoxy-phenyl)-3-methyl-quinoxaline 131.2 mg (0.4 mmol), Iron(III) chloride hexahydrate 2.7 mg (0.01 mmol), Potassium Persulphate 216 mg(0.8 mmol), N,N-dimethylacetamide (4 mL) adds in the 25 mL flasks.110 ℃ of reactions of mixture heating up TLC detection reaction end after 3 hours, wash with saturated aqueous common salt (10 mL ⅹ 3) after adding the dilution of 20 mL ether, organic phase with anhydrous sodium sulfate drying after decompression slough solvent, obtaining weak yellow liquid 2-(2-bromo-4-p-methoxy-phenyl with column chromatography chromatogram method (the leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 15 ︰ 1) separation)-3-vinyl quinoxaline 118.3 mg(87% yields).
[3] with 2-(2-bromo-4-p-methoxy-phenyl)-3-vinyl quinoxaline 51.0 mg (0.15 mmol), tetrakis triphenylphosphine palladium 7.3 mg(0.0075 mmol), Sulfuric acid disilver salt 94 mg(0.3 mmol) add successively in the dry reaction pipe of 10 mL.Be filled with argon gas after reaction tubes vacuumized, repeatable operation three times, under argon atmosphere with needle cylinder injection triethylamine 61 mg(0.6 mmol) and degassed dry N,N-dimethylacetamide 2 mL.With mixture reacting by heating 2 hours in 140 ℃ of oil baths.After the TLC detection reaction finishes, reaction solution is rear with saturated aqueous common salt (10 mL ⅹ 3) washing with the dilution of 15 mL ether, organic phase with anhydrous sodium sulfate drying after decompression slough solvent, obtaining yellow solid 3-methoxyl group benzo [α] azophenlyene 32.4 mg(83% yields with column chromatography chromatogram method (the leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 15 ︰ 1) separation).
Yellow solid; R
f=0.28 (petroleum ether-EtOAc=6:1); Mp=166-167 ℃;
1H NMR (500 MHz, CDCl
3): δ=9.30 (d, J=8.5 Hz, 1H), 8.33 (dd, J
1=7.3 Hz, J
2=2.3 Hz, 1H), 8.27 (dd, J
1=7.3 Hz, J
2=2.3 Hz, 1H), 7.96 (d, J=9.0 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.87-7.82 (m, 2 H), 7.38 (dd, J
1=9.0 Hz, J
2=2.5 Hz, 1H), 7.28 (d, J=2.5 Hz, 1H), 4.00 (s, 3H) ppm;
13C NMR (125 MHz, CDCl
3): δ=161.1,142.8,142.7,142.1,142.0,134.9,133.2,129.8,129.6,129.5,129.1,127.6,127.2,124.8,117.1,109.7,55.6 ppm; MS (EI, 70eV): m/z (%)=260 (100) [M+], 245 (7).
Embodiment 3
[1] with 2-naphthyl ethyl ketone (5 g), O-methyl hydroxylamine (4 g), reflux stirs and spends the night in the 15 mL pyridines adding methyl alcohol, reaction finishes to be cooled to room temperature, steam under the decompression and add 50mL water in the backward residue of solvent, use extracted with diethyl ether, obtain 2-naphthalene acetone-O-methyloxime (yield 82 %) with the separation of column chromatography chromatogram method behind the organic phase drying precipitation.With 2-naphthalene acetone-O-methyloxime (5.0 mmol), NBS (5.5 mmol), Pd(OAc)
2(0.25 mmol) joins in the 30 mL acetic acid, mixture is 100 ℃ of lower stirrings 12 hours, decompression obtained 3-bromo-2-naphthalene acetone-O-methyloxime (yield 84 %) with the separation of column chromatography chromatogram method after steaming solvent after question response finished, 3-bromo-2-naphthalene acetone-O-methyloxime (5.0 mmol) adds 1 of 15 mL hydrogenchloride, in 80 ℃ of lower heating 4 hours (TLC detection to reaction finishes), the separation of column chromatography chromatogram method obtained 3-bromo-2-naphthyl ethyl ketone (yield 87 %) after decompression steamed solvent in 4-dioxane (5M) solution.
[2] with 3-bromo-2-naphthyl ethyl ketone (5.0 mmol), be dissolved in the 5mL methylene dichloride, drip bromine (6.0 mmol) under the room temperature, wait to dropwise and continued stirring reaction 60 minutes, add the saturated sodium thiosulfate solution washing in the system after colourless, separatory is got the dry removal of solvent under reduced pressure of organic phase and is obtained alpha-brominated 3-bromo-2-naphthyl ethyl ketone crude product, need not to purify and directly carries out ring closure reaction.Alpha-brominated 3-bromo-2-naphthyl ethyl ketone with the dissolving of 10mL acetonitrile, is added HClO4SiO2(350 mg) and formula V shown in substituted o-phenylenediamine (10 mmol), mixture is at 60 ℃ of lower stirring reactions, TLC detects to the reaction end.Mixture after filtration, separate with column chromatography chromatogram method (the leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 15 ︰ 1) behind the filtrate decompression desolvation obtain faint yellow solid 2-(3-bromo-2-naphthyl)-3-methyl-quinoxaline 1.04g (yield 60 %).
[3] with 2-(3-bromo-2-naphthyl)-3-methyl-quinoxaline 139.2 mg (0.4 mmol), Iron(III) chloride hexahydrate 2.7 mg (0.01 mmol), Potassium Persulphate 216 mg(0.8 mmol), N,N-dimethylacetamide (4 mL) adds in the 25 mL flasks.110 ℃ of reactions of mixture heating up TLC detection reaction end after 3 hours, wash with saturated aqueous common salt (10 mL ⅹ 3) after adding the dilution of 20 mL ether, organic phase with anhydrous sodium sulfate drying after decompression slough solvent, obtaining weak yellow liquid 2-(3-bromo-2-naphthyl with column chromatography chromatogram method (the leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 15 ︰ 1) separation)-3-vinyl quinoxaline 125.3 mg(87% yields).
[4] with 2-(3-bromo-2-naphthyl)-3-vinyl quinoxaline 54.0 mg (0.15 mmol), tetrakis triphenylphosphine palladium 7.3 mg(0.0075 mmol), Sulfuric acid disilver salt 94 mg(0.3 mmol) add successively in the dry reaction pipe of 10 mL.Be filled with argon gas after reaction tubes vacuumized, repeatable operation three times, under argon atmosphere with needle cylinder injection triethylamine 61 mg(0.6 mmol) and degassed dry N,N-dimethylacetamide 2 mL.With mixture reacting by heating 2 hours in 140 ℃ of oil baths.After the TLC detection reaction finishes, reaction solution is rear with saturated aqueous common salt (10 mL ⅹ 3) washing with the dilution of 15 mL ether, organic phase with anhydrous sodium sulfate drying after decompression slough solvent, obtain yellow solid naphtho-[2,3-α] azophenlyene 34.4 mg(82% yields with column chromatography chromatogram method (the leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 15 ︰ 1) separation).
Yellow solid; R
f=0.43 (petroleum ether-EtOAc=6:1); Mp=225-226 ℃;
1H NMR (500 MHz, CDCl
3): δ=9.80 (s, 1H), 8.37-8.35 (m, 1H), 8.28-8.23 (m, 3H), 8.05 (dd, J
1=8.5 Hz, J
2=3.5 Hz, 1 H), 7.98 (d, J=9.5 Hz, 1H), 7.88-7.83 (m, 2H), 7.78 (d, J=9.5 Hz, 1H), 7.65-7.62 (m, 2H) ppm;
13C NMR (125 MHz, CDCl
3): δ=144.6,144.0,142.4,141.6,134.2,133.7,132.4,130.8,129.8,129.7,129.5,129.3,129.0,128.9,128.1,127.3,127.2,127.1,126.7,125.7 ppm; MS (EI, 70eV): m/z (%)=280 (100) [M+].
Claims (10)
1. the method for synthetic replacement benzo [α] azophenlyene compounds shown in formula III, it is characterized in that described method is: take the 2-halogenated aryl ethyl ketone shown in the formula IV as raw material, after α-bromination, carry out ring-closure reaction with the substituted o-phenylenediamine shown in the formula V, 2-(2-halogenated aryl shown in the synthesis type I)-the 3-methyl-quinoxaline, 2-(2-halogenated aryl shown in the formula I)-the 3-methyl-quinoxaline in the presence of iron catalyst and oxygenant with the reaction of N-methyl nitrosourea shown in the formula VI, 2-(2-halogenated aryl shown in the production II)-3-vinyl quinoxaline, 2-(2-halogenated aryl shown in the formula II)-3-vinyl quinoxaline carries out the Heck ring closure reaction under the palladium catalyst effect, generate replacement benzo [α] the azophenlyene compounds shown in the formula III;
Among formula I, formula II, formula III or the formula IV, R
1, R
2, R
3, R
4Independent separately is H, methyl, methoxyl group, phenyl, F, Cl, Br, I, NO
2, CF
3, COOCH
3, COOC
2H
5, CN; Or R
2, R
3Connect into ring with its two carbon that connect on the phenyl ring, form a new phenyl ring;
Among formula I, formula II, formula III or the formula V, R
5, R
6, R
7, R
8Independent separately is H, methyl, Cl, phenyl or COO CH
3
Among formula I, formula II or the formula IV, X is Cl, Br or I;
Among the formula VI, R is H, methyl or phenyl.
2. the method for claim 1 is characterized in that said method comprising the steps of:
(1) the 2-halogenated aryl ethyl ketone shown in the formula IV is dissolved the rear bromine simple substance that splashes into ether or methylene dichloride under room temperature, dropwised under room temperature stirring reaction 15 ~ 60 minutes, then in reaction mixture, add the saturated sodium thiosulfate solution washing to colourless, separatory is got the organic phase drying, the decompression desolvation, the gained crude product is alpha-brominated 2-halogenated aryl ethyl ketone, and crude product is dissolved with acetonitrile, adds HClO
4SiO
2Substituted o-phenylenediamine shown in catalyzer and the formula V, at room temperature stirring reaction under the reflux temperature, TLC follows the tracks of to detect to reaction and finishes, gained reaction solution a aftertreatment obtains the 2-(2-halogenated aryl shown in the formula I)-the 3-methyl-quinoxaline; 2-halogenated aryl ethyl ketone shown in the described formula IV is 1:1.0 ~ 1.5 with the ratio of the amount of substance of bromine simple substance; Described alpha-brominated 2-halogenated aryl ethyl ketone is 1:1 ~ 5 with the ratio of the amount of substance of the substituted o-phenylenediamine shown in the formula V; The amount of substance of described alpha-brominated 2-halogenated aryl ethyl ketone comes in the amount of substance of the 2-halogenated aryl ethyl ketone shown in the formula IV;
(2) the 2-(2-halogenated aryl shown in the formula I)-the 3-methyl-quinoxaline is in the presence of iron catalyst and oxygenant, with the N-methyl nitrosourea reaction shown in the formula VI, 20 ~ 160 ℃ of temperature of reaction, TLC follows the tracks of and detects to the reaction end, and the reaction solution aftertreatment obtains the 2-(2-halogenated aryl shown in the formula II)-3-vinyl quinoxaline; Described iron catalyst is molysite or ferrous salt, and described oxygenant is persulphate,, the 2-(2-halogenated aryl shown in the described formula I)-ratio of the amount of substance of 3-methyl-quinoxaline, iron catalyst, oxygenant is 1:0.001 ~ 0.3:1 ~ 5; 2-(2-halogenated aryl shown in the described formula I)-concentration of 3-methyl-quinoxaline in the N-methyl nitrosourea shown in the formula VI is 0.01 ~ 2mol/L;
(3) the 2-(2-halogenated aryl shown in the formula II)-3-vinyl quinoxaline and palladium catalyst, inorganic silver salt additives be in inert gas environment, add tertiary amine compounds and polar non-proton organic solvent, under 50 ~ 160 ℃ temperature of reaction, carry out the Heck ring closure reaction, TLC follows the tracks of and detects to the reaction end, and the reaction solution separating treatment obtains replacement benzo [α] the azophenlyene compounds shown in the formula III; Described palladium catalyst is tetrakis triphenylphosphine palladium or three (dibenzalacetone) two palladiums, the 2-(2-halogenated aryl shown in the described formula II)-ratio of the amount of substance of 3-vinyl quinoxaline, palladium catalyst, inorganic silver salt additives, tertiary amine compounds is 1:0.001 ~ 0.15:1 ~ 4:1 ~ 10.
3. method as claimed in claim 2, it is characterized in that in the described step (2), described iron catalyst is iron trichloride, ferric sulfate, iron nitrate, ferric acetyl acetonade, ferrous sulfate, iron protochloride, Iron(III) chloride hexahydrate, Iron dichloride tetrahydrate, Fe(NO3)39H2O or ferrous sulfate.
4. method as claimed in claim 2 is characterized in that in the described step (2), described oxygenant is ammonium persulphate, Potassium Persulphate, Sodium Persulfate or potassium hydrogen persulfate composite salts.
5. method as claimed in claim 2, it is characterized in that in the described step (2), the reaction solution post-treating method is: after reaction finishes, reacting liquid filtering, filtrate add the ether dilution, after the saturated common salt water washing, get to steam after the organic phase drying and desolventize, residuum is through column chromatography for separation, take sherwood oil or hexanaphthene and ethyl acetate by volume the solvent that mixes of 2 ~ 30:1 as eluent, collect elutriant steam desolventize the 2-(2-halogenated aryl that obtains shown in the formula II)-3-vinyl quinoxaline.
6. method as claimed in claim 2 is characterized in that in the described step (3), described tertiary amine compounds is triethylamine, Tri-n-Propylamine or DIPEA.
7. method as claimed in claim 2 is characterized in that in the described step (3), described inorganic silver salt additives is Sulfuric acid disilver salt or Silver Nitrate.
8. method as claimed in claim 2 is characterized in that in the described step (3), described polar non-proton organic solvent is N,N-dimethylacetamide or DMF.
9. method as claimed in claim 2, it is characterized in that in the described step (3), described reaction solution method for separating and processing is: after reaction finishes, reacting liquid filtering, filtrate add the ether dilution, after the saturated common salt water washing, get to steam after the organic phase drying and desolventize, residuum is through column chromatography for separation, take sherwood oil and ethyl acetate by volume the solvent that mixes of 2 ~ 30:1 collect elutriant and steam and desolventize replacement benzo [α] the azophenlyene compounds that obtains shown in the formula III as eluent.
10. such as claim method as claimed in claim 2, it is characterized in that in the described step (3), described rare gas element is argon gas or nitrogen.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210363571.2A CN102898388B (en) | 2012-09-26 | 2012-09-26 | Method for synthesizing substituted benzo[alpha]phenazine compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210363571.2A CN102898388B (en) | 2012-09-26 | 2012-09-26 | Method for synthesizing substituted benzo[alpha]phenazine compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102898388A true CN102898388A (en) | 2013-01-30 |
| CN102898388B CN102898388B (en) | 2014-12-03 |
Family
ID=47570908
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210363571.2A Active CN102898388B (en) | 2012-09-26 | 2012-09-26 | Method for synthesizing substituted benzo[alpha]phenazine compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102898388B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106083713A (en) * | 2016-07-15 | 2016-11-09 | 浙江工业大学 | A kind of chemical synthesis process of quinoline () quinoline 2 benzaldehyde compound |
| CN106558654A (en) * | 2015-09-30 | 2017-04-05 | 北京鼎材科技有限公司 | A kind of phenonaphthazine derivant and its application in organic electroluminescence device |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0676393B2 (en) * | 1986-09-27 | 1994-09-28 | 大正製薬株式会社 | Benzo [α-phenazine derivative |
| CN1433406A (en) * | 1999-12-02 | 2003-07-30 | 埃克森诺瓦有限公司 | Benzo[a]henazin-11-carboxamide derivatives and their use as joint inhibitors of topomerase I and II |
| US20040185297A1 (en) * | 2003-03-18 | 2004-09-23 | Eastman Kodak Company | Cascaded organic electroluminescent devices |
| CN102206189A (en) * | 2011-04-14 | 2011-10-05 | 四川大学 | Method for preparing phenazine compound by catalyzing o-halogeno aniline in water phase |
-
2012
- 2012-09-26 CN CN201210363571.2A patent/CN102898388B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0676393B2 (en) * | 1986-09-27 | 1994-09-28 | 大正製薬株式会社 | Benzo [α-phenazine derivative |
| CN1433406A (en) * | 1999-12-02 | 2003-07-30 | 埃克森诺瓦有限公司 | Benzo[a]henazin-11-carboxamide derivatives and their use as joint inhibitors of topomerase I and II |
| US20040185297A1 (en) * | 2003-03-18 | 2004-09-23 | Eastman Kodak Company | Cascaded organic electroluminescent devices |
| CN102206189A (en) * | 2011-04-14 | 2011-10-05 | 四川大学 | Method for preparing phenazine compound by catalyzing o-halogeno aniline in water phase |
Non-Patent Citations (4)
| Title |
|---|
| BO QIAN等: "Palladium-Catalyzed Benzylic Addition of 2-Methyl Azaarenes to N-Sulfonyl Aldimines via C-H Bond Activation", 《J. AM. CHEM. SOC.》, vol. 132, no. 11, 2 March 2010 (2010-03-02), pages 3650 - 3651 * |
| JINNHO KIM等: "Copper-Mediated Selective Cyanation", 《ORGANIC LETTERS》, vol. 14, no. 15, 13 July 2012 (2012-07-13), pages 3924 - 3927 * |
| JINNHO KIM等: "Copper-Mediated Sequential Cyanation of Aryl C−B and Arene C−H Bonds Using Ammonium Iodide and DMF", 《J. AM. CHEM. SOC.》 * |
| JINNHO KIM等: "Copper-Mediated Sequential Cyanation of Aryl C−B and Arene C−H Bonds Using Ammonium Iodide and DMF", 《J. AM. CHEM. SOC.》, vol. 134, no. 5, 24 January 2012 (2012-01-24), pages 2528 - 2531 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106558654A (en) * | 2015-09-30 | 2017-04-05 | 北京鼎材科技有限公司 | A kind of phenonaphthazine derivant and its application in organic electroluminescence device |
| CN106558654B (en) * | 2015-09-30 | 2020-01-14 | 北京鼎材科技有限公司 | Benzophenazine derivative and application thereof in organic electroluminescent device |
| CN106083713A (en) * | 2016-07-15 | 2016-11-09 | 浙江工业大学 | A kind of chemical synthesis process of quinoline () quinoline 2 benzaldehyde compound |
| CN106083713B (en) * | 2016-07-15 | 2019-07-26 | 浙江工业大学 | A kind of chemical synthesis process of quinoline () quinoline -2- benzaldehyde compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102898388B (en) | 2014-12-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Zhou et al. | Propargylamines formed from three-component coupling reactions catalyzed by silver oxide nanoparticles | |
| Gao et al. | A Lewis acid-promoted reduction of acylsilanes to α-hydroxysilanes by diethylzinc | |
| Qiu et al. | Synthesis of highly rigid phosphine–oxazoline ligands for palladium-catalyzed asymmetric allylic alkylation | |
| CN103420860B (en) | Method for compounding amino-substituted arylate compound | |
| CN102898388B (en) | Method for synthesizing substituted benzo[alpha]phenazine compound | |
| Amadio et al. | A new palladium (II)–allyl complex containing a thioether-triazole ligand as active catalyst in Suzuki–Miyaura reaction. Use of tetraalkylammonium salts as promoters: Influence of the salt anion and cation on the catalytic activity | |
| Xie et al. | Design and synthesis of new chiral pyridine–phosphite ligands for the copper-catalyzed enantioselective conjugate addition of diethylzinc to acyclic enones | |
| CN113149915B (en) | Method for synthesizing clonazepam compound | |
| CN109422700A (en) | A kind of synthetic method of N- acetyl group quinoxaline -2- amide and its derivative | |
| CN106986886B (en) | A kind of preparation method of the fluoro- 3- Trifluoromethoxyphen-l pinacol borate of 4- | |
| Patti et al. | Parallel or classical kinetic resolution of a planar chiral ferrocenylketone through asymmetric reductions | |
| CN102382058A (en) | Preparation method of N-aryl-heterocyclic nitrogen compound | |
| CN109422680A (en) | A kind of synthetic method of N- acetylquinoline -2- amide and its derivative | |
| EP3227018B1 (en) | Chelation directed c-h activation reactions catalyzed by solid-supported palladium(ii) catalysts | |
| CN103333123B (en) | Dehalogenation method for dihydrogen quinazoline ketone compound | |
| CN103694182B (en) | A kind of preparation method of quinoxaline compound | |
| CN112500337B (en) | Synthetic method of 3-bromo-6-chloropyridine formamide | |
| WO2007089193A1 (en) | A process for preparing 2-hydroxy-3- [5- (morpholin-4-ylmethyl)pyridin-2-yl] lh-indole-5-carbonitrile as a free base or salts thereof | |
| CN102329281B (en) | C-acyl-dihydro sulfinpyrazone based on catalysis of chiral bicyclic imidazole nucleophilic catalyst and preparation method thereof | |
| CN108383697A (en) | A method of preparing deuterated aldehyde by raw material of halomethyl compounds | |
| Ma et al. | An efficient Pd-catalyzed coupling of hydrazine derivatives with aryl halides | |
| Kalita et al. | A three-component synthesis of homoallylic amines catalyzed by CuI | |
| CN102977040B (en) | Method for synthesizing 2-quinoxalinyl dimethylacetal and 2-quinoxalinyl formaldehyde | |
| CN102718694B (en) | 3-cyan substituted indole compound and synthetic method thereof | |
| CN112939829A (en) | Synthetic method of aryl trifluoromethyl thioether |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |